PROJECT SUMMARY Obesity increases the risk of kidney cancer. But, paradoxically, clinical studies of kidney cancer patients find that obese patients actually live longer than those with lower body mass index (BMI). This counter-intuitive phenomenon is known as the ?obesity paradox.? One interpretation of the obesity paradox is that excess weight benefits kidney cancer patients; therefore, obese kidney cancer patients should stay heavy to increase survival. However, this interpretation is in direct opposition to national guidelines that advise weight loss for obese cancer patients. Instead, we believe that the obesity paradox could result from inadequate study design and analytic strategies. Specifically, previous studies that compared weight status and survival among kidney cancer patients did not account for (1) disease-related weight loss before diagnosis, (2) kidney cancer risk factors that are stronger predictors of mortality than obesity is, and (3) obesity-related kidney cancer subtypes that may have more favorable prognosis than other subtypes. If any of these biases are present then, ?Association does not equal causation,? and the results from prior research do not address how weight-related interventions could affect RCC survival. No prior study has accounted for these biases when studying the obesity paradox in kidney cancer patients. Fortunately, by using longitudinal data to study kidney cancer patients before they get the disease and special statistical techniques that can account for cancer risk factors that increase mortality, we can estimate how excess weight actually affects kidney cancer survival. Using the NIH-AARP Diet and Health Study, the Specific Aims are: 1) Among prevalent RCC cases, perform a sensitivity analysis to quantify the degree to which pre-diagnosis weight loss and collider bias could affect the crude association between BMI and 5-year survival, and 2) Among incident RCC cases, use inverse-probability weighting (IPW) to estimate the association between pre-diagnosis BMI and mortality adjusted for collider stratification bias. Resolving the controversy around the RCC ?obesity paradox? requires an explicitly causal framework, appropriate analytic methods, and a rich, longitudinal data set like the NIH-AARP Diet and Health Study. By combining all of these elements, we will produce results that get to the heart of the RCC paradox and provide the basis for future obesity-related interventions to improve survival for RCC patients. Further, if our analyses demonstrate and eliminate biases in RCC survivorship research, then this project will introduce a new approach that shifts the paradigm of methods used in observational research on cancer survival.